The orphan receptor GPR83 regulates systemic energy metabolism via ghrelin-dependent and -independent mechanisms

Abstract

The G-protein coupled receptor 83 (GPR83) is an orphan G-protein coupled receptor (GPCRs) that is highly expressed in thymus and brain. Within the brain GPR83 expression can especially be found in hypothalamic nuclei that are known to play an important role in body weight regulation. We explore a putative role for GPR83 in energy metabolism. By doing this we demonstrate that hypothalamic expression of GPR83 is decreased in diet-induced obese (DIO) mice compared to lean mice. Additionally, hypothalamic expression is reduced following fasting and increased upon re-feeding. Via in situ hybridization it could be shown that GPR83 is co-localized with the ghrelin receptor (GHSR1a). In vitro studies could confirm GPR83/GHSR1a heterodimerization. Functional characterization of the heterodimer suggests that GPR83 leads to a reduced activation of GHSR1a by its ligand ghrelin. In agreement, studies in GPR83-knockout mice show that loss of GPR83 potentiates the effect of both, central and peripheral ghrelin treatment, on food intake and adiposity. GPR83-knockout mice have normal body weight and glucose tolerance when fed a regular chow diet. Glucose intolerance and obesity were not observed in response to high-fat diet despite relative hyperphagia. In summary, our data suggest that GPR83 acts as a modulator of ghrelin action in response to nutrient availability. In addition to these findings GPR83 seems to play a more complex role in the regulation of systemic metabolism.